In this project, our goals are to elaborate the details of an evaluate the significance of new pathways of corticosteroid metabolism. We have shown in all species studied, including man, that the ketol side chain is reversibly converted by an isomerase to an aldol configuration that can undergo further changes. Interconversion of the 20alpha and 20beta epimeric forms of the aldol is catalyzed by an epimerase. Either epimer is oxidixzed to the hydroxy acid side chain (cortoic acids in man) by aldehyde dehydrogenases or reduced to glycols (cortols and cortolones in man) by aldol reductase. The properties of the enzymes that catalyze these changes, isolated from the livers of hamsters and mice, are being studied in detail in order to develop a basis for understanding how the various pathways of corticosteroid metabolism are controlled and coordinated. In parallel studiesin humans, metabolic pathways coresponding to those in animals are inferred from the urinary metabolites derived from intravenously injected precursors. The metabolic and clinicopathological significance in man of the expanded pathways of corticosteroid metabolism are under study. For these purposes, analytical techniques are being developed to measure cortoic acids in blood and urine. Genetic techniques are being utilized to determine the contribution of heredity to individual differences in the formation of cortoic acids. We have observed that isomerase activity in mouse liver is under genetic control. Linkage to the major histocompatibility complex locus, H-2, corresponding in man to the HLA locus, is inferred from breeding data. In order to evaluate the clinical significance of this linkage to HLA, an important study is specifically directed to patients with congenital adrenal hyperplasia.